Cough-variant asthma (CVA) occurs in a subgroup of asthmatics whose sole or predominant respiratory symptom is cough. Although bronchodilators are often sufficient to treat CVA, refractory cough may require therapy with inhaled or systemic corticosteroids. In a randomized, double-blind, placebo-controlled, crossover study, we examined the effect of a 14-day course of the leukotriene receptor antagonist zafirlukast on subjective cough score and cough-reflex sensitivity to inhaled capsaicin in eight subjects with CVA refractory to inhaled beta agonists, and in five subjects refractory to inhaled corticosteroids. Seven of eight subjects experienced significant subjective and objective improvement in cough after treatment with zafirlukast. Mean (+/- SEM) cough score improved from 7.75 +/- 0.56 to 3.25 +/- 0.84 (p = 0.0006). Cough sensitivity to capsaicin was suppressed by zafirlukast in all subjects. Patients with CVA may represent a distinct subgroup of asthmatics whose afferent cough receptors within the respiratory epithelium are hypersensitive relative to those of patients with the typical form of asthma. Zafirlukast appears to be particularly effective in treating CVA by inhibiting the sensitivity of these receptors. Leukotriene receptor antagonists may offer an alternative to corticosteroids for the treatment of CVA refractory to inhaled bronchodilators.

No abstract

Gamma-aminobutyric acid (GABA) is a central inhibitory neurotransmitter that also exists in the lungs. The GABA-agonist baclofen has been shown to have antitussive activity via a central mechanism in animals. Recently it was demonstrated that a 14-day course of baclofen given three times daily significantly inhibits the cough reflex in healthy volunteers. Because of the prolonged antitussive effect of baclofen that has been previously observed, the present study was conducted to evaluate the antitussive effect of low-dose, oral baclofen given once daily. Forty-one healthy volunteers were randomly assigned in a double-blind manner to receive a 28-day course of baclofen, either 10 mg or 20 mg once daily, or placebo. Subjects underwent cough challenge testing with inhaled capsaicin to establish baseline cough reflex sensitivity, and subsequently after 14 and 28 days of therapy. Subjects receiving baclofen 20 mg daily demonstrated significant inhibition of cough sensitivity after 14 days and after 28 days of therapy compared with baseline. Neither placebo nor baclofen 10 mg daily had a significant effect on cough sensitivity. No serious side effects were experienced by any study participant. These results confirm the recent observation that baclofen has significant antitussive activity in humans. Further, once-daily administration of a relatively low dose of baclofen is sufficient to achieve significant cough inhibition, although at least 14 to 28 days of therapy may be required to attain maximal antitussive effect. These results support further investigation of baclofen or other GABA-agonists as potential therapeutic agents for chronic, nonproductive cough.

In patients with asthma, increased sensitivity of airway sensory nerves may be involved in producing bronchospasm and cough. To evaluate the effect of a leukotriene-modifying agent on cough reflex sensitivity, we measured the cough response to inhaled capsaicin before and after a 1 4-day course of therapy with zafirlukast, a cysteinyl leukotriene receptor antagonist, in a group of stable asthmatics. The concentration of capsaicin inducing two or more (C2) and five or more (C5) coughs was not altered by zafirlukast, even in those subjects demonstrating a significant change (increment or decrement) in forced expiratory volume in 1 sec (FEV1). These findings support previous evidence that cough and bronchoconstriction are modulated by distinct neural pathways.

Gamma-aminobutyric acid (GABA) levels in the CSF were measured in 9 normal individuals, 17 drug-free schizophrenic patients and 10 of these same schizophrenic patients after neuroleptic treatment. There was no significant difference between CSF level of GABA in the control group compared to those in schizophrenic patients; however, 6 of the 7 lowest GABA levels were from schizophrenic patients. There was a significant decline of 12 per cent in mean GABA levels in the CSF after a mean of two months of neuroleptic treatment.

Abstract— A method for the separation and determination of γ‐aminobutyrylcholine (GABACh) from trichloracetic acid treated brain extracts has been developed. It consists of the separation of the extracts on Dowex 1 × 8 columns, precipitation of the quaternary ammonium bases and their separation by paper chromatography. Using this technique it was found that electrical stimulation for 30 s of one brachial plexus in the cat resulted in 4.6 fold increase in GABACh concentration in the stimulated (contralateral) cerebral cortex as compared to the non‐stimulated (ipsilateral) cortex. This change in GABACh concentration was not reversed within 5 s of cessation of the stimulus. The results are discussed in relation to the possible physiological role of GABACh: (a) as a neurotransmitter; (b) as a substance participating in the inactivation process of GABA. The possible connection of GABACh to the metabolism of GABA and acetylcholine is discussed.

A simple method is described for the measurement of free brain glutamine by spectrophotometric means, without prior separation by either paper or column chromatography. Through the application of this method, it was also possible to obtain an approximate value for the combined concentrations of glutamic acid, 7-aminobutyric acid and glutathione in brain.

For detecting field carcinogenesis non-invasively, early technical development and case–control testing of exhaled breath condensate microRNAs was performed. In design, human lung tissue microRNA-seq discovery was reconciled with TCGA and published tumor-discriminant microRNAs, yielding a panel of 24 upregulated microRNAs. The airway origin of exhaled microRNAs was topographically “fingerprinted”, using paired EBC, upper and lower airway donor sample sets. A clinic-based case–control study (166 NSCLC cases, 185 controls) was interrogated with the microRNA panel by qualitative RT-PCR. Data were analyzed by logistic regression (LR), and by random-forest (RF) models. Feasibility testing of exhaled microRNA detection, including optimized whole EBC extraction, and RT and qualitative PCR method evaluation, was performed. For sensitivity in this low template setting, intercalating dye-based URT-PCR was superior to fluorescent probe-based PCR (TaqMan). In application, adjusted logistic regression models identified exhaled miR-21, 33b, 212 as overall case–control discriminant. RF analysis of combined clinical + microRNA models showed modest added discrimination capacity (1.1–2.5%) beyond clinical models alone: all subjects 1.1% (p = 8.7e−04)); former smokers 2.5% (p = 3.6e−05); early stage 1.2% (p = 9.0e−03), yielding combined ROC AUC ranging from 0.74 to 0.83. We conclude that exhaled microRNAs are qualitatively measureable, reflect in part lower airway signatures; and when further refined/quantitated, can potentially help to improve lung cancer risk assessment.